Assembly, Trafficking and Function of -Secretase

-Secretase catalyzes the final cleavage of the -amyloid precursor protein to generate amyloidpeptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer’s disease. Here, we review the identification of -secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, -secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2 and APH-1 that are essential and sufficient for -secretase activity. PS, which serves as a catalytic subunit of -secretase, was identified as a prototypic member of novel aspartyl proteases of the GxGD type. In human cells, -secretase could be further defined as a heterogeneous activity consisting of distinct complexes that are composed of PS1 or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2. Using green fluorescent protein as a reporter we localized PS and -secretase activity at the plasma membrane and endosomes. Investigation of secretase complex assembly in knockdown and knockout cells of the individual subunits allowed us to develop a modD i s e a s e s Dr. Christoph Kaether Group ‘Membrane trafficking of proteins involved in Alzheimer’s Disease’ Leibniz Institute for Age Research – Fritz Lipmann Institute Beutenbergstrasse 11, DE–07745 Jena (Germany) Tel. +49 3641 65 6230, Fax +49 3641 65 6040, E-Mail [email protected] © 2006 S. Karger AG, Basel 1660–2854/06/0035–0275$23.50/0 Accessible online at: www.karger.com/ndd 1 Co-corresponding author: [email protected]